| It was reported that most of cancer patients are suffering nausea and vomiting in chemotherapy. Chemotherapy-induced nausea and vomiting (CINV) affects many cancer patients and has a great influence on quality of life. Ondansetron is a highly selective serotonin 5-HT3 receptor-antagonist available as an antiemetic drug and it is also helpful during the treatment and/or prevention of nausea and vomiting caused by emetic cancer chemotherapy, radiotherapy, anesthesia, and surgery. Herein, as the first class of selective serotonin 5-HT3 receptor antagonists, Ondansetron has been widely developed and applied in clinic.Ondansetron are mostly used by oral or injection administration. The conventional dosage forms are tablets, orally disintegrating tablets, capsules and injections. However, these products clinically showed limited efficacy. It is reported that the oral bioavailability was about 60% due to considerable hepatic and intestinal first-pass effects in rats and the biological half life was only about 3 h. Besides, common tablets and capsules have the shortage of dosing frequency that cause great inconvenience to the patients with dysphasia and vomiting. Ondansetron injections in high dosage can cause serious cardiac arrhythmias such as QT prolongation, intravenous administration may also cause side effects and unexpected accidents. In recent years, various formulation approaches have been developed to improve oral bioavailability and patient compliance such as oral mucosal adhesive tablets, dispersible tablets, and floating sustained release tablets. There are also new delivery systems being utilized like microemulsions, nanoparticles, nanovesicular systems, nasal delivery systems and fast-release filmsFast-release films are attracting more and more interests in the pharmaceutical industry. The buccal film drug delivery system, in most cases, is a film containing active ingredient that can dissolve or disintegrate in the saliva within a few seconds and without the need for water or chewing. In such cases, bioavailability of Ondansetron is significantly developed than conventional tablet since the oral or buccal mucosa is highly vascularized. Drugs can be absorbed directly into blood, which could avoid first-pass hepatic metabolism and the degradation in the gastrointestinal (GI) tract. Fast-release film of Ondansetron Hydrochloride have the advantages of rapid drug release, low risk of choking and obstruction which can improve patients’compliance, especially for the disabled bedridden, the dysphagic, the elderly or the pediatric patients.The formulation of solid dispersion use hydrophilic carrier can be used to improve the dissolution and bioavailability of drugs. Also, the drug is dispersed as amorphous, microcrystalline or molecular patterns, which primarily increase the level of drugs and reduce the adverse reactions.Sublingual administration of the drug means placement of the drug under the tongueand drug reaches directly in to the blood stream through the ventral s urface of the tongue and floor of the mouth. The drug solutes are rapidly absorbed int o the reticulated vein which lies underneath the oral mucosa, and transported t hrough the facial veins, internal jugular vein, and braciocephalic vein and then drained in to systemic circulation. The films of containing Ondansetron Hydrochloride is administrated in Sublingual, thus reduce the first pass metabolism and may increase the bioavailability of drug. It can be consumed no need of water which have great compliance. The study include the research of film-forming materials; the evaluation of Ondansetron Hydrochloride films and pharmacokinetics study of the films in rats.1. Studies of on the basic film-forming formulationsThe method to determine the Ondansetron Hydrochloride was established in vitro. The equilibrium solubility and octanol-water partition coefficient of Ondansetron Hydrochloride in different media were determined using HPLC. The equilibrium solubility of Ondansetron Hydrochloride in pH 1.0 HCl, pH 6.8 PBS were 7.35、1.02 mg·mL-1 which conform to the request of sink condition. The octanol-water partition coefficient of Ondansetron Hydrochloride in pH 1.0 HCl, pH 6.8 PBS were-0.909,1.19, indicating the drug was more liposoluble in pH 6.8 condition. The appropriate concentration range of polymers, plasticizers and modifiers was studies by scoring method. The compatibility between the drug and excipients in films was evaluated by physical and chemical means.2. Optimization of Ondansetron Hydrochloride films formulationThe basic film-forming materials were studied through single factor tests and the crystal inhibitors were optimized using solid dispersion technique. The ratio of drug and polymers were optimized by DSC and XRD which revealed there was no presence of crystal in the optimized solid dispersion. In vitro release studies and showed the dissolution rate of solid dospersion with PVP K30 was faster than that of PVP K90. The solvent of polymers, weight ratio of HPMC to XG, weight ratio of Drug to PVP, weight ratio of Drug to PEG were choosen as the factors, which were optimized by orthogonal design taken the drug released in 30min as index. The optimized formulation was using 50% EtOH as solvent. The weight ratio of HPMC to XG was 40:1. The weight ratio of Drug to PVP was 1:1 and the weight ratio of Drug to PEG was 3:4.3. Preparation and Evaluation of Ondansetron Hydrochloride filmsOn the basis of former study, the Ondansetron Hydrochloride fast release films were prepared. The films were evaluated in appearance, physical character, drug content and stability. The results showed that, the final film was white thin films and was smooth in surface without obvious bubbles or cracks. Mean weight of each film was 40-50mg. Mean thichness was 60-70μm. Surface pH was 6.4～6.6. The films could release 85% of drug with 1.5min in O.lmol/L HCl and within 30min in pH6.8PBS. The results of of drug content uniformity test indicated the films met the criteria of CP2010. FT-IR、XRD、DSC、SEM evaluation revealed no crystal for Ondansetron Hydrochloride in final films. The preparation was packaged within Aluminum-plastic bags in vaccum and stored in accelerated condition to study the stability of quality. The existing data showed that there was no significant changes for the appearance, content and drug release of films.4. Studies of pharmacolinetics of Ondansetron Hydrochloride films in ratsThe pharmacolinetic experiment of Ondansetron Hydrochloride solution, marketed films Zuplenz(?) and the preparation were carried out in rats. LC-MS/MS method of determining the drug in plasma was established. The plasma samples was precipitated protein before analyzing. The result showed that AUC of the preparation was significantly gteater than that of oral solution and the marketed films, and the drug was absorbed faster. This may be due to the decrease of fast pass effect in sublingual administration.In this study, the films of Ondansetron Hydrochloride were developed which had the advantages of fast drug release, improved patient compliance, higher bioavalibility. The quality stability was confirmed in six mouths which achieved the pre-designed objective of the product. |
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